Beta-catenin is a molecular target of the Fanconi anemia core complex

β-连环蛋白是范可尼贫血核心复合物的分子靶标

基本信息

批准号：
8680357
负责人：
Kim-Hien T Dao
金额：
$ 12.83万
依托单位：
OREGON HEALTH & SCIENCE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-26 至 2017-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8680357
关键词：
Acute Myelocytic Leukemia Acute leukemia Advisory Committees Animals Area Automobile Driving Award Binding Biological Biological Assay Blood California Cancer Biology Cell Death Cell Line Cells Cellular biology Clinical Clonal Evolution Complement Complex Confocal Microscopy Cycloheximide DNA Damage Data Defect Development Development Plans Disease Disease Progression Disease model Doctor of Philosophy Environment Extramural Activities Fanconi anemia protein Fanconi&apos s Anemia Fellowship Funding Genes Genetic Goals Health Sciences Hematology Hematopoietic stem cells Human Individual Inferior Inherited Institutes Internal Medicine K-Series Research Career Programs Longevity Maintenance Malignant - descriptor Medical Medicine Mentors Molecular Molecular Target Mono-S Natural Selections Nuclear Nuclear Extract Oregon Outcome Pancytopenia Pathway interactions Patients Phase Post-Translational Protein Processing Predisposition Principal Investigator Process Property Protein Tyrosine Kinase Proteins Regenerative Medicine Reporter Research Research Personnel Research Project Grants Residencies Role Scientific Advances and Accomplishments Scientist Signal Transduction Stem Cell Development Stem cells Testing Training Transgenic Organisms Tumor Necrosis Factor-alpha Ubiquitination United States National Institutes of Health Universities Western Blotting base beta catenin cancer cell career career development experience fitness improved functioning in vivo Model loss of function mutation mouse model mutant oncology outcome forecast overexpression prevent programs protein complex response sarcoma stem cell biology ubiquitin-protein ligase

项目摘要

DESCRIPTION (provided by applicant): The proposed K08 career development award application describes a 5-year program for the support of the principal investigator, Dr. Kim-Hien Dao, who is a clinician scientist in the transitional phases of developing an independent research program at Oregon Health & Science University (OHSU). Dr. Dao's research experience began with her PhD training in the area of cancer biology and RAS signaling in human fibro sarcoma cell lines. After Internal Medicine residency training, she completed fellowship training in Hematology-Oncology at the University of California at San Diego. Through this experience, as a Clinical Fellow Scholar in the California Institute for Regenerative Medicine Program, she acquired a 2-year postdoctoral research experience under the direction of Dr. Catriona Jamieson and was introduced to hematopoietic stem cell biology. The current application outlines additional years of mentored research with a formal career development plan under the guidance of Drs. Grover Bagby and Brian Druker. Dr. Dao will take advantage of an advisory committee composed of highly successful, NIH-funded medical scientists at OHSU and a research environment with internationally-recognized expertise in Fanconi Anemia (FA) research, stem cell biology, cancer cell biology, and tyrosine kinase signaling. The research proposed will focus on investigating why loss of function mutations in genes of the FA pathway, classically described as a DNA damage response pathway, give rise to hematopoietic stem cells with inherent defects in stem cell fitness. The overall hypothesis is that the FA core complex is involved in stabilizing the nuclear function of beta-catenin and the disruption of this interaction is the molecular basis for the limited replicative and survival potential of FA deficiet hematopoietic stem cells. The main objective is to mechanistically define the interaction between FA pathway and Wnt/beta-catenin signaling. The specific aims include: 1) Determine whether proteins of the FA core complex increase protein stability and/or nuclear localization of beta-catenin; 2) Determine whether FANCL directly mono-ubiquitinates beta-catenin leading to its enhanced nuclear activity; and 3) Define specific perturbations in Wnt/beta-catenin signaling in FA-deficient hematopoietic stem cells during development and bone marrow failure in an in vivo model of FA. If the susceptible pool of hematopoietic stem cells to malignant clonal evolution is defined by deficient Wnt/beta-catenin signaling, then disease progression in patients with bone marrow failure might be subverted by manipulating targets of the Wnt/beta-catenin pathway that would restore the fitness of the hematopoietic stem cells in a selective microenvironment. The mentored K08 award will directly advance her scientific development by protecting her effort towards her research project and career development plan. These transitional steps are necessary for her to achieve her long-term career goal of becoming a productive, independent researcher in academic medicine with sustained extramural funding.

描述（由申请人提供）：拟议的 K08 职业发展奖申请描述了一个为期 5 年的计划，旨在支持首席研究员 Kim-Hien Dao 博士，他是一名临床科学家，正处于开发独立研究计划的过渡阶段俄勒冈健康与科学大学 (OHSU)。 Dao 博士的研究经历始于她在癌症生物学和人类纤维肉瘤细胞系 RAS 信号传导领域的博士培训。完成内科住院医师培训后，她在加州大学圣地亚哥分校完成了血液肿瘤学专科培训。通过这段经历，她作为加州再生医学研究所的临床研究员，在 Catriona Jamieson 博士的指导下获得了 2 年的博士后研究经验，并了解了造血干细胞生物学。当前的申请概述了在博士的指导下额外几年的指导研究和正式的职业发展计划。格罗弗·巴格比和布莱恩·德鲁克。 Dao 博士将利用 OHSU 的由 NIH 资助的非常成功的医学科学家组成的咨询委员会以及在范可尼贫血 (FA) 研究、干细胞生物学、癌细胞生物学和酪氨酸激酶方面具有国际公认专业知识的研究环境发信号。拟议的研究将重点调查为什么 FA 途径（通常被描述为 DNA 损伤反应途径）基因功能缺失突变会导致造血干细胞具有干细胞适应性的固有缺陷。总体假设是 FA 核心复合物参与稳定 β-连环蛋白的核功能并破坏该功能。相互作用是 FA 缺陷的造血干细胞复制和生存潜力有限的分子基础。主要目标是从机制上定义 FA 通路和 Wnt/β-catenin 信号传导之间的相互作用。具体目标包括： 1) 确定 FA 核心复合物的蛋白质是否增加蛋白质稳定性和/或 β-catenin 的核定位； 2) 确定FANCL是否直接单泛素化β-catenin导致其核活性增强； 3) 定义 FA 体内模型中 FA 缺陷造血干细胞在发育和骨髓衰竭过程中 Wnt/β-catenin 信号传导的特定扰动。如果造血干细胞对恶性克隆进化的敏感池是由 Wnt/β-连环蛋白信号传导缺陷定义的，那么骨髓衰竭患者的疾病进展可能会通过操纵 Wnt/β-连环蛋白通路的靶标来逆转，从而恢复骨髓衰竭患者的疾病进展。造血干细胞在选择性微环境中的适应性。受指导的 K08 奖将通过保护她对研究项目和职业发展计划的努力，直接促进她的科学发展。这些过渡步骤对于她实现长期职业目标是必要的，即成为一名富有成效的、独立的学术医学研究人员，并获得持续的校外资助。